目的 制备高乌甲素自胶束化固体分散体缓释片（lappaconitine-self-micellizing solid dispersion sustained-release tablets，Lap-SMSD-SRT），考察其体内药动学及毒动学。方法 溶剂挥发法制备Lap-SMSD粉末，研究其基本理化性质。单因素实验考察羟丙基甲基纤维素（hydroxypropyl methyl cellulose，HPMC）K4M、羧甲基淀粉钠（carboxymethyl starch Na，CMS-Na）和乳糖用量对Lap-SMSD-SRT释药行为的影响。采用Lap-SMSD-SRT在2、6、12 h累积释放率综合评分为响应值，Box-Behnken设计-响应面法（Box-Behnken design-response surface method，BBD-RSM）优化Lap-SMSD-SRT处方。比较氢溴酸高乌甲素片、高乌甲素普通片和Lap-SMSD-SRT的体外释药行为。取6只Beagle犬，采用3周期交叉试验考察药动学行为，计算Lap-SMSD-SRT的相对生物利用度。设置Lap-SMSD-SRT低、中、高（0.75、1.50、2.25 mg/kg）3个剂量组，给药期和恢复期均为4周，比较首次和末次给药后血浆中高乌甲素含量，计算毒动学参数。观察动物生活状态，检查血液学和生化指标。结果 Lap-SMSD中聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物（Soluplus）和高乌甲素用量比为5∶1，分散于水中可迅速形成粒径为（29.44±2.01）nm的胶束。Lap-SMSD-SRT最佳处方：HPMC K4M用量为19.09%，CMS-Na用量为15.59%，乳糖用量为22.63%。Lap-SMSD-SRT在2、6、12 h累积释放率分别为26.50%、61.67%和93.67%。药动学结果显示，Lap-SMSD-SRT达峰时间（t_max）延后至（6.20±1.61）h，半衰期（t_1/2）延长至（9.13±2.64）h，达峰浓度（C_max）增加至（123.94±46.77）ng/mL，Lap-SMSD-SRT相对生物利用度提高至5.21倍。Lap-SMSD-SRT各剂量在Beagle犬体内均未见明显的高乌甲素蓄积现象。Lap-SMSD-SRT中、高剂量组可能对血液系统和肝脏有轻微影响，4周恢复期症状消失。结论 Lap-SMSD-SRT工艺重复性良好，缓释特征明显，显著促进了高乌甲素体内吸收，使用安全性良好。

Objective Lappaconitine-self-micellizing solid dispersion sustained-release tablets (Lap-SMSD-SRT) was prepared, and investigated its pharmacokinetics and toxicokinetics in vivo. Methods Lap-SMSD powder was prepared by solvent evaporation method, and its basic physicochemical properties were also studied. The influence of hydroxypropyl methyl cellulose (HPMC) K4M dosage, carboxymethyl starch sodium (CMS-Na) dosage and lactose dosage on the drug release behavior of Lap-SMSD-SRT were investigated by single factor experiments. Composite score of cumulative release rate at 2, 6, 12 h was used as response value, Box-Behnken design-response surface method (BBD-RSM) was employed to optimize formulation of Lap-SMSD-SRT. The release behavior of lappaconitine hydrobromide tablets, lappaconitine tablets and Lap-SMSD-SRT were compared. Six beagle dogs were used to study the pharmacokinetic behavior by a three-period crossover trial, and the relative bioavailability of Lap-SMSD-SRT was calculated. Three level of low, medium, high (0.75, 1.50, 2.25 mg/kg) dose groups of Lap-SMSD-SRT were set up, and compared the plasma concentration of lappaconitine after the first and last administration with a 4-week dosing period and a 4-week recovery period. Then the toxicokinetic parameters were calculated. The living condition of Beagle dogs was observed, and the hematology and biochemical indexes were also examined. Results The dosage ratio of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus) to lappaconitine in Lap-SMSD powder was 5:1, and quickly became into micelles with particle size of (29.44 ± 2.01) nm when dispersed in water. Optimal formulation of Lap-SMSD-SRT: HPMC K4M dosage was 19.09%, CMS-Na dosage was 15.59%, and lactose dosage was 22.63%. The cumulative release rate of Lap-SMSD-SRT at 2, 6, 12 h were 26.50%, 61.67% and 93.67%, respectively. Pharmacokinetic results showed that the peak time (t_max) of Lap-SMSD-SRT was delayed to (6.20 ± 1.61) h, the half-life (t_1/2) was prolonged to (9.13 ± 2.64) h, the peak concentration (C_max) was enhanced to (123.94 ± 46.77) ng/mL, and the relative bioavailability was enhanced to 5.21-fold. No significant accumulation of lappaconitine was observed in Beagle dogs at each dose of Lap-SMSD-SRT. There might be slight effect on the blood system and liver in the medium-dose and high-dose groups of Lap-SMSD-SRT, but these symptoms disappeared during the 4-week recovery period. Conclusion The preparation process of Lap-SMSD-SRT was reproducible, and the formulation exhibited obvious sustained-release characteristics, significantly enhanced the in vivo absorption of lappaconitine, and showed good safety.

R283.6

2024年度河南省科技攻关项目（242102110111）